Method for treating or preventing psychosomatic and psychoimmunologic disorders

ABSTRACT

A tachykinin receptor antagonist is useful for treating or preventing a psychosomatic or a psychoimmunological disorder in a patient.

BACKGROUND OF THE INVENTION

[0001] The fact that psychologic stress can precipitate or alter thecourse of organic diseases has long been recognized. An essentialchallenge in psychosomatic-psychobiological research is to delineate themechanisms by which experience causes certain types of physiologicalreactions that result in disease states. In addition, the mechanisms ofneurobiological modulating systems need to be understood at themolecular and genetic levels. Recent and ongoing developments incellular and molecular biology provide some research models by whichtransducing mechanisms involved in psychosomatic reactions can beunderstood at the most fundamental level. It has been suggested thatanxiety can occur as a result of acquired neurophysiologicalchemosensitivity. Stimuli that produce “chronic anxiety” in the seasnail aplysia cause the enhancement of connections made by the sensoryneurons on their target cells—that is, interneurons and motor neurons.The enhancing process, deemed postsynaptic facilitation, is caused bynoxious stimuli that activate cells that use a serotonin-likeneurotransmitter. Those cells on the head of the aplysia act as adefensive arousal system, impinge on the synaptic terminals of thereflex system for gill withdrawal, and enhance the connections that thesensory synapses make on the motor neurons and interneurons. Serotoninappears to play a major role in the defensive arousal process byincreasing intracellular cAMP, which then strengthens theneuroconnectors of the sensory neurons by facilitating neurotransmitterrelease. In accordance with the present invention, substance P has beenfound to play an important role in the inducement of disease states bypsychobiological reactions.

[0002] With respect to psychoimmunologic disorders, interest in theinteractions between the central nervous system and the immune systemdate back to Aristotle, who hypothesized a connection between physicalhealth and mood. Later, Sir William Osler spoke of the importance ofknowing what is going on in a patient's head, as well as the lungs, inpredicting the outcome of pulmonary tuberculosis. During the mid 1950sSelye demonstrated a clear relation among brain activity, endocrineorgans, and immune function. In 1964 the field was first referred to aspsychoimmunology, later amended to psychoneuroimmunology, the study ofthe interaction of consciousness, the brain and the central nervoussystem, and the body's immune system. In recent years major advanceshave been made in establishing direct evidence for a brain-immune systemrelation. In serving functions of adaptation and defense, both thecentral nervous system and the immune system discriminate between selfand nonself, and they incorporate principles of recognition, learning,memory, and transmission of information. Evidence for such acommunication system ranges from anatomical confirmation of the centralnervous system innervation of immune organs to reports documenting thebehavioral effects on immune response and tumor acquisition inexperimental animals. A number of studies involving experimental animalsand human autopsy specimens have shown direct sympathetic nervous systeminnervation of the spleen, the thymus, and the lymph nodes. Cholinergicinnervation of the thymus gland has now been documented, andinvestigators have described noradrenergic innervation of lymphoidtissue in a variety of mammalian species, including humans.

[0003] Lending further evidence is the presence of receptors for variousneurotransmitters, neurohormones, and neuropeptides on cells of theimmune system. In particular, neurokinin receptors have been found inlymphatic tissue. Noradrenergic receptors have been found on lymphocytesthat appear to be exclusively for beta2-adrenergic receptors, which aresimilar to those found in the smooth muscles of the bronchi and thelungs. In addition to the noradrenergic receptors of the beta-1 subtype,evidence indicates the presence on lymphocytes of receptors for gonadalsteroids, endorphins, enkephalins, corticotropin, vasointestinalpeptide, cholecystokinin, neurotensin, acetylcholine, and serotonin.Recent evidence also indicates that lymphocytes may synthesize someneurohormones de novo.

[0004] Although some studies suggest that bereavement and depression caninterfere with immunological competence, the findings in this area ofresearch have been diverse and often inconsistent. Studies of bereavedmen and women have reported reduced in vitro lymphocyte response tomitogen stimulation, with normal levels of circulating immunoglobulinsand normal responses on delayed hypersensitivity skin tests; the reducedlymphocyte response is most dramatic in bereaved patients withdepressive symptoms. A recent meta-analysis of methodologically soundstudies addressing cellular immunity in depression found that the immuneabnormalities reliably associated with depression were (1) decreasedproliferative response of lymphocytes to mitogen stimulation, (2)decreased natural killer cell activity, and (3) abnormalities ofdifferent white blood cell lines. The magnitude of these immune systemabnormalities correlated with the intensity of depressed mood. However,methodological concerns limit the interpretation and generalizability ofmuch of the available data on the immune system in depression; there isa high incidence of failure to replicate findings.

[0005] Although the present invention is not limited to a specificmechanism of action, the inventors postulate that a potentialexplanation for some of the diverse findings may involve highcatecholamine output and the increased production of prostaglandins,each of which has been observed separately in studies of depressedpatients. Catecholamines, acting through beta-adrenergic receptors, areknown to suppress the activity of human natural killer cells.Prostaglandins, functioning through a complex interaction between secondmessenger systems, may inhibit in vitro mitogen-induced lymphocyteproliferation. Because recent animal work suggests that prostaglandinproduction is increased by catecholamines through a nonreceptor-mediatedmechanism, the diminished immunological competence reported in depressedpatients may be a result of the dysregulation of the catecholaminergicsystem. In accordance with the present invention, the neuropeptidesubstance P is postulated to play in important role in this mechanism.Accordingly, a tacykinin antagonist, in particular a neurokinin-1receptor antagonist would be useful in the treatment or prevention of apsychosomatic disorder or a psychoimmunologic disorder.

[0006] Antidepressant and antianxiety agents have been employed forpsychosomatic or psychoimmunologic disorders with limited success. Inaddition, certain side effects may be present with such treatment. Theseapproaches have had limited success, however, and an alternate means oftreating or preventing psychosomatic or psychoimmunologic disorderswould be of great benefit.

[0007] The neuropeptide receptors for substance P (neurokinin-1; NK-1)are widely distributed throughout the mammalian nervous system(especially brain and spinal ganglia), the circulatory system andperipheral tissues (especially the duodenum and jejunum) and areinvolved in regulating a number of diverse biological processes. Thisincludes sensory perception of olfaction, vision, audition and pain,movement control, gastric motility, vasodilation, salivation, andmicturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK-1 andNK-2 receptor subtypes are implicated in synaptic transmission(Laneuville et al., Life Sci., 42, 1295-1305 (1988)).

[0008] Substance P is a naturally occurring undecapeptide belonging tothe tachykinin family of peptides, the latter being so-named because oftheir prompt contractile action on extravascular smooth muscle tissue.The tachykinins are distinguished by a conserved carboxyl-terminalsequence. In addition to SP the known mammalian tachykinins includeneurokinin A and neurokinin B. The current nomenclature designates thereceptors for substance P, neurokinin A, and neurokinin B asneurokinin-1, neurokinin-2, and neurokinin-3, respectively.

[0009] Substance P is a pharmacologically-active neuropeptide that isproduced in mammals and acts as a vasodilator, a depressant, stimulatessalivation and produces increased capillary permeability. It is alsocapable of producing both analgesia and hyperalgesia in animals,depending on dose and pain responsiveness of the animal (see R. C. A.Frederickson et al., Science 199, 1359 (1978); P. Oehme et al. Science,208, 305 (1980)) and plays a role in sensory transmission and painperception (T. M. Jessell, Advan. Biochem. Psvchopharmacol. 28, 189(1981)).

[0010] Neurokinin-1 (NK-1; substance P) receptor antagonists are beingdeveloped for the treatment of a number of physiological disordersassociated with an excess or imbalance of tachykinins, and in particularsubstance P. Examples of conditions in which substance P has beenimplicated include disorders of the central nervous system such asanxiety, depression and psychosis (see, for instance, PCT PatentPublication Nos. WO 95/16679, WO 95/18124 and WO 95/23798). Morerecently, PCT Patent Publication No WO 96/24353 suggests that a moreefficacious and safe treatment of psychiatric disorders would beachieved using a combination of a tachykinin antagonist and a serotoninagonist or selective serotonin reuptake inhibitor (SSRI). However, suchas regimen would not be free of side-effects due to the serotoninagonist or SSRI. Currently there are only limited means for treating orpreventing psychosomatic or psychoimmunologic disorders. In view of theshort- comings of existing agents, there is a need for new effectivemethods for treating or preventing psychosomatic and psychoimmunologicdisorders.

SUMMARY OF THE INVENTION

[0011] The present invention relates to the use of a tachykinin receptorantagonist, in particular a neurokinin-1 receptor antagonist, for thetreatment or prevention of a psychosomatic disorder or apsychoimmunologic disorder or the amelioration of symptoms attendant toa psychosomatic disorder or a psychoimmunologic disorder comprising theadministration of a tachykinin antagonist, in particular a neurokinin-1receptor antagonist. In a preferred embodiment, the present inventionprovides a method for treatment or prevention of a psychosomaticdisorder or a psychoimmunologic disorder or the amelioration of symptomsattendant to a psychosomatic disorder or a psychoimmunologic disordercomprising the administration of a tachykinin receptor antagonist, inparticular a neurokinin-1 receptor antagonist.

DESCRIPTION OF THE INVENTION

[0012] The present invention is directed to a method for treating orpreventing a psychosomatic disorder in a patient comprising theadministration of a tachykinin receptor antagonist, in particular anNK-1 receptor antagonist.

[0013] The present invention is further directed to a method fortreating or preventing a psychoimmunologic disorder in a patientcomprising the administration of a tachykinin receptor antagonist, inparticular an NK-1 receptor antagonist.

[0014] The present invention is further directed to a method forameliorating the symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient comprising the administration ofa tachykinin receptor antagonist, in particular an NK-1 receptorantagonist.

[0015] In a preferred embodiment, the present invention provides amethod for treating or preventing a psychosomatic disorder in a patientcomprising the administration of a tachykinin receptor antagonist, inparticular an NK-1 receptor antagonist. In a more preferred embodiment,the present invention provides a method for diminishing or severing thedetrimental influence of psychological stimuli in a disease or disorderfor which the physical etiology is contributed to directly or indirectlyby psychological factors.

[0016] In a preferred embodiment, the present invention provides amethod for treating or preventing a psychoimmunologic disorder in apatient comprising the administration of a tachykinin receptorantagonist, in particular an NK-1 receptor antagonist. In a morepreferred embodiment, the present invention provides a method fordiminishing or severing the direct or indirect detrimental influence ofpsychological stimuli on the immunological state of a patient byemploying an NK-1 receptor antagonist.

[0017] In a preferred embodiment, the present invention further providesa method for ameliorating the symptoms attendant to a psychosomaticdisorder or a psychoimmunologic disorder in a patient comprising theadministration of a tachykinin receptor antagonist, in particular anNK-1 receptor antagonist.

[0018] The present invention further provides a pharmaceuticalcomposition for treating or preventing a psychosomatic disorder or apsychoimmunologic disorder in a patient comprising a tachykinin receptorantagonist, in particular an NK-1 receptor antagonist, together with atleast one pharmaceutically acceptable carrier or excipient.

[0019] The present invention further provides a pharmaceuticalcomposition for ameliorating the symptoms attendant to a psychosomaticdisorder or a psychoimmunologic disorder in a patient comprising atachykinin receptor antagonist, in particular an NK-1 receptorantagonist, together with at least one pharmaceutically acceptablecarrier or excipient.

[0020] In accordance with the present invention the tachykinin receptorantagonist is administered to a patient in a quantity sufficient totreat or prevent the symptoms and/or underlying etiology associated withthe psychosomatic or psychoimmunologic disorder in a patient.

[0021] In a further aspect of the present invention, there is provided apharmaceutical composition for treating or preventing a psychosomaticdisorder or a psychoimmunologic disorder in a patient comprising a NK-1receptor antagonist, together with at least one pharmaceuticallyacceptable carrier or excipient.

[0022] In a further aspect of the present invention, there is provided apharmaceutical composition ameliorating the symptoms attendant to apsychosomatic disorder or a psychoimmunologic disorder in a patientcomprising a NK-1 receptor antagonist, together with at least onepharmaceutically acceptable carrier or excipient.

[0023] The present invention also provides the use of a NK-1 receptorantagonist for the manufacture of a medicament for treating orpreventing a psychosomatic disorder or a psychoimmunologic disorder in apatient.

[0024] The present invention also provides the use of a NK-1 receptorantagonist for the manufacture of a medicament for ameliorating thesymptoms attendant to a psychosomatic disorder or a psychoimmunologicdisorder in a patient.

[0025] It is well recognized in the art that psychological stimuli canprecipitate or alter the course of numerous diseases or disorders. Asused herein a “psychosomatic disorder” is a disease or disorder forwhich the physical etiology is contributed to directly or indirectly bypsychological factors. As used herein a “psychoimmunologic disorder” isan immunologic disease or disorder wherein an immunological response isinfluenced directly or indirectly by psychological factors.

[0026] Although the present invention is useful in any mammal sufferingfrom psychosomatic disorder or a psychoimmunologic disorders, apreferred subject is a human.

[0027] The tachykinin receptor antagonists of use in the presentinvention may be any tachykinin antagonist known from the art.Preferably, the tachykinin receptor antagonist is a neurokinin-1 (NK-1)or neurokinin-2 (NK-2) receptor antagonist, especially a neurokinin-1(NK-1) receptor antagonist.

[0028] The tachykinin antagonist may be peptidal or non-peptidal innature, however, the use of a non-peptidal tachykinin receptorantagonist is preferred. In addition, for convenience the use of anorally active tachykinin receptor antagonist is preferred.

[0029] In the present invention, it is preferred that the tachykininreceptor antagonist is active upon the central nervous system (CNS),such as the brain, following systemic administration, i.e. that itreadily penetrates the CNS. Accordingly, a preferred tachykininantagonist for use in the present invention is a CNS-penetratingtachykinin antagonist, especially a CNS-penetrating NK-1 antagonist. Anespecially preferred class of NK-1 receptor antagonist of use in thepresent invention are those compounds which are orally active, longacting and CNS-penetrant.

[0030] Neurokinin-1 receptor antagonists of use in the present inventionare fully described, for example, in U.S. Pat. Nos. 5,162,339,5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926,5,496,833, 5,637,699; European Patent Publication Nos. EP 0 360 390, 0394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0585 913,0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCTInternational Patent Publication Nos. WO 90/05525, 90/05729, 91/09844,91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661,92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165,93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113,93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440,94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496,94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170,94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323,94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042,95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311,95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819,95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744,96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939,96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328,96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144,97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and inBritish Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. Thepreparation of such compounds is fully described in the aforementionedpatents and publications.

[0031] Particularly preferred NK-1 receptor antagonists are thosedescribed in PCT International Patent Publication No. WO 95/16679 andEuropean Patent Publication No. 0 577 394 as compounds of formula (I):

[0032] or a pharmaceutically acceptable salt thereof, wherein:

[0033] R¹ is selected from the group consisting of:

[0034] (1) hydrogen;

[0035] (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0036] (a) hydroxy,

[0037] (b) oxo,

[0038] (c) C₁₋₆ alkoxy,

[0039] (d) phenyl-C₁₋₃ alkoxy,

[0040] (e) phenyl,

[0041] (f) —CN,

[0042] (g) halo, wherein halo is fluoro, chloro, bromo or iodo,

[0043] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

[0044] (i) hydrogen,

[0045] (ii) C₁₋₆ alkyl,

[0046] (iii) hydroxy-C 16 alkyl, and

[0047] (iv) phenyl,

[0048] (i) —NR⁹COR¹⁰,

[0049] (j) —NR⁹CO²R¹⁰,

[0050] (k) —CONR⁹R¹⁰,

[0051] (l) —COR⁹,

[0052] (m) —CO²R⁹,

[0053] (n) heterocycle, wherein the heterocycle is selected from thegroup consisting of:

[0054] (A) benzimidazolyl,

[0055] (B) benzofuranyl,

[0056] (C) benzothiophenyl,

[0057] (D) benzoxazolyl,

[0058] (E) furanyl,

[0059] (F) imidazolyl,

[0060] (G) indolyl,

[0061] (H) isooxazolyl,

[0062] (I) isothiazolyl,

[0063] (J) oxadiazolyl,

[0064] (K) oxazolyl,

[0065] (L) pyrazinyl,

[0066] (M) pyrazolyl,

[0067] (N) pyridyl,

[0068] (O) pyrimidyl,

[0069] (P) pyrrolyl,

[0070] (Q) quinolyl,

[0071] (R) tetrazolyl,

[0072] (S) thiadiazolyl,

[0073] (T) thiazolyl,

[0074] (U) thienyl,

[0075] (V) triazolyl,

[0076] (W) azetidinyl,

[0077] (X) 1,4-dioxanyl,

[0078] (Y) hexahydroazepinyl,

[0079] (Z) piperazinyl,

[0080] (AA) piperidinyl,

[0081] (AB) pyrrolidinyl,

[0082] (AC) tetrahydrofuranyl, and

[0083] (AD) tetrahydrothienyl,

[0084] and wherein the heterocycle is unsubstituted or substituted withone or more substituent(s) selected from:

[0085] (i) C₁₋₆ alkyl, unsubstituted or substituted with halo, —CF₃,—OCH₃, or phenyl,

[0086] (ii) C₁₋₆ alkoxy,

[0087] (iii) oxo,

[0088] (iv) hydroxy,

[0089] (v) thioxo,

[0090] (vi) —SR⁹,

[0091] (vii) halo,

[0092] (viii) cyano,

[0093] (ix) phenyl,

[0094] (x) trifluoromethyl,

[0095] (xi) —(CH₂)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2,

[0096] (xii) —NR⁹COR¹⁰,

[0097] (xiii) —CONR⁹R¹⁰,

[0098] (xiv) —CO₂R⁹, and

[0099] (xv) —(CH₂)_(m)—OR⁹;

[0100] (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0101] (a) hydroxy,

[0102] (b) oxo,

[0103] (c) C₁₋₆alkoxy,

[0104] (d) phenyl-C₁₋₃ alkoxy,

[0105] (e) phenyl,

[0106] (f) —CN,

[0107] (g) halo,

[0108] (h) —CONR⁹R¹⁰,

[0109] (i) —COR⁹,

[0110] (j) —CO₂R⁹,

[0111] (k) heterocycle;

[0112] (4) C₂₋₆ alkynyl;

[0113] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0114] (a) hydroxy,

[0115] (b) C₁₋₆ alkoxy,

[0116] (c) C₁₋₆ alkyl,

[0117] (d) C₂₋₅ alkenyl,

[0118] (e) halo,

[0119] (f) —CN,

[0120] (g) —NO₂,

[0121] (h) —CF₃,

[0122] (i) —(CH₂)_(m)—NR⁹R¹⁰,

[0123] (j) —NR⁹COR¹⁰,

[0124] (k) —NR⁹CO₂R¹⁰,

[0125] (l) —CONR⁹R¹⁰,

[0126] (m) —CO₂NR⁹R¹⁰,

[0127] (n) —COR⁹,

[0128] (o) —CO₂R⁹;

[0129] R² and R³ are independently selected from the group consistingof:

[0130] (1) hydrogen,

[0131] (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0132] (a) hydroxy,

[0133] (b) oxo,

[0134] (c) C₁₋₆ alkoxy,

[0135] (d) phenyl-C₁₋₃ alkoxy,

[0136] (e) phenyl,

[0137] (f) —CN,

[0138] (g) halo,

[0139] (h) —NR⁹R¹⁰,

[0140] (i) —NR⁹COR¹⁰,

[0141] (k) —CONR⁹R¹⁰,

[0142] (l) —COR⁹, and

[0143] (m) —CO₂R⁹;

[0144] (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0145] (a) hydroxy,

[0146] (b) oxo,

[0147] (c) C₁₋₆ alkoxy,

[0148] (d) phenyl-C₁₋₃ alkoxy,

[0149] (e) phenyl,

[0150] (f) —CN,

[0151] (g) halo,

[0152] (h) —CONR⁹R¹⁰,

[0153] (i) —COR⁹, and

[0154] (j) —CO₂R⁹;

[0155] (4) C₂₋₆ alkynyl;

[0156] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0157] (a) hydroxy,

[0158] (b) C₁₋₆ alkoxy,

[0159] (c) C₁₋₆ alkyl,

[0160] (d) C₂₋₅ alkenyl,

[0161] (e) halo,

[0162] (f) —CN,

[0163] (g) —NO₂,

[0164] (h) —CF₃,

[0165] (i) —(CH₂)_(m)—NR⁹R¹⁰,

[0166] (j) —NR⁹COR¹⁰,

[0167] (k) —NR⁹CO₂R¹⁰,

[0168] (l) —CONR⁹R¹⁰,

[0169] (m) —CO₂NR⁹R¹⁰,

[0170] (n) —COR⁹, and

[0171] (o) —CO₂R⁹;

[0172] and the groups R¹ and R² may be joined together to form aheterocyclic ring selected from the group consisting of:

[0173] (a) pyrrolidinyl,

[0174] (b) piperidinyl,

[0175] (c) pyrrolyl,

[0176] (d) pyridinyl,

[0177] (e) imidazolyl,

[0178] (f) oxazolyl, and

[0179] (g) thiazolyl,

[0180] and wherein the heterocyclic ring is unsubstituted or substitutedwith one or more substituent(s) selected from:

[0181] (i) C₁₋₆alkyl,

[0182] (ii) oxo,

[0183] (iii) C₁₋₆alkoxy,

[0184] (iv) —NR⁹R¹⁰,

[0185] (v) halo, and

[0186] (vi) trifluoromethyl;

[0187] and the groups R² and R³ may be joined together to form acarbocyclic ring selected from the group consisting of:

[0188] (a) cyclopentyl,

[0189] (b) cyclohexyl,

[0190] (c) phenyl,

[0191] and wherein the carbocyclic ring is unsubstituted or substitutedwith one or more substituents selected from:

[0192] (i) C₁₋₆alkyl,

[0193] (ii) C₁₋₆alkoxy,

[0194] (iii) —NR⁹R¹⁰,

[0195] (iv) halo, and

[0196] (v) trifluoromethyl;

[0197] and the groups R² and R³ may be joined together to form aheterocyclic ring selected from the group consisting of:

[0198] (a) pyrrolidinyl,

[0199] (b) piperidinyl,

[0200] (c) pyrrolyl,

[0201] (d) pyridinyl,

[0202] (e) imidazolyl,

[0203] (f) furanyl,

[0204] (g) oxazolyl,

[0205] (h) thienyl, and

[0206] (i) thiazolyl,

[0207] and wherein the heterocyclic ring is unsubstituted or substitutedwith one or more substituent(s) selected from:

[0208] (i) C₁₋₆alkyl,

[0209] (ii) oxo,

[0210] (iii) C₁₋₆alkoxy,

[0211] (iv) —NR⁹R¹⁰,

[0212] (v) halo, and

[0213] (vi) trifluoromethyl;

[0214] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0215] (1) hydrogen;

[0216] (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0217] (a) hydroxy,

[0218] (b) oxo,

[0219] (c) C₁₋₆ alkoxy,

[0220] (d) phenyl-C₁₋₃ alkoxy,

[0221] (e) phenyl,

[0222] (f) —CN,

[0223] (g) halo,

[0224] (h) —NR⁹R¹⁰,

[0225] (i) —NR⁹COR¹⁰,

[0226] (j) —NR⁹CO₂R¹⁰,

[0227] (k) —CONR⁹R¹⁰,

[0228] (l) —COR⁹, and

[0229] (m) —CO₂R⁹;

[0230] (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0231] (a) hydroxy,

[0232] (b) oxo,

[0233] (c) C₁₋₆ alkoxy,

[0234] (d) phenyl-C₁₋₃ alkoxy,

[0235] (e) phenyl,

[0236] (f) —CN,

[0237] (g) halo,

[0238] (h) —CONR⁹R¹⁰,

[0239] (i) —COR⁹, and

[0240] (j) —CO₂R⁹;

[0241] (4) C₂₋₆ alkynyl;

[0242] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0243] (a) hydroxy,

[0244] (b) C₁₋₆ alkoxy,

[0245] (c) C₁₋₆ alkyl,

[0246] (d) C₂₋₅ alkenyl,

[0247] (e) halo,

[0248] (f) —CN,

[0249] (g) —NO₂,

[0250] (h) —CF₃,

[0251] (i) —(CH₂)_(m)—NR⁹R¹⁰,

[0252] (j) —NR⁹COR¹⁰,

[0253] (k) —NR⁹CO₂R¹⁰,

[0254] (l) —CONR⁹R¹⁰,

[0255] (m) —CO₂NR⁹R¹⁰,

[0256] (n) —COR⁹,

[0257] (o) —CO₂R⁹;

[0258] (6) halo,

[0259] (7) —CN,

[0260] (8) —CF₃,

[0261] (9) —NO₂,

[0262] (10) —SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅alkyl,

[0263] (11) —SOR¹⁴,

[0264] (12) —SO₂R¹⁴,

[0265] (13) NR⁹COR¹⁰,

[0266] (14) CONR⁹COR¹⁰,

[0267] (15) NR⁹R¹⁰,

[0268] (16) NR⁹CO₂R¹⁰,

[0269] (17) hydroxy,

[0270] (18) C₁₋₆alkoxy,

[0271] (19) COR⁹,

[0272] (20) CO₂R⁹,

[0273] (21) 2-pyridyl,

[0274] (22) 3-pyridyl,

[0275] (23) 4-pyridyl,

[0276] (24) 5-tetrazolyl,

[0277] (25) 2-oxazolyl, and

[0278] (26) 2-thiazolyl;

[0279] R¹¹, R¹² and R¹³ are independently selected from the definitionsof R⁶, R⁷ and R⁸;

[0280] X is selected from the group consisting of:

[0281] (1) —O—,

[0282] (2) —S—,

[0283] (3) —SO—, and

[0284] (4) —SO₂—;

[0285] Y is selected from the group consisting of:

[0286] (1) a single bond,

[0287] (2) —O—,

[0288] (3) —S—,

[0289] (4) —CO—,

[0290] (5) —CH₂—,

[0291] (6) —CHR¹⁵—, and

[0292] (7) —CR¹⁵R¹⁶—, wherein R¹⁵ and R¹⁶ are independently selectedfrom the group consisting of:

[0293] (a) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0294] (i) hydroxy,

[0295] (ii) oxo,

[0296] (iii) C₁₋₆ alkoxy,

[0297] (iv) phenyl-C₁₋₃ alkoxy,

[0298] (v) phenyl,

[0299] (vi) —CN,

[0300] (vii) halo,

[0301] (viii) —NR⁹R¹⁰,

[0302] (ix) —NR⁹COR¹⁰,

[0303] (x) —NR⁹CO₂R¹⁰,

[0304] (xi) —CONR⁹R¹⁰,

[0305] (xii) —COR⁹, and

[0306] (xiii) —CO₂R⁹;

[0307] (b) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0308] (i) hydroxy,

[0309] (ii) C₁₋₆ alkoxy,

[0310] (iii) C₁₋₆ alkyl,

[0311] (iv) C₂₋₅ alkenyl,

[0312] (v) halo,

[0313] (vi) —CN,

[0314] (vii) —NO₂,

[0315] (viii) —CF₃,

[0316] (ix) —(CH₂)_(m)—NR⁹R¹⁰,

[0317] (x) —NR⁹COR¹⁰,

[0318] (xi) —NR⁹CO₂R¹⁰,

[0319] (xii) —CONR⁹R¹⁰,

[0320] (xiii) —CO₂NR⁹R¹⁰,

[0321] (xiv) —COR⁹, and

[0322] (xv) —CO₂R⁹; and

[0323] Z is C₁₋₆ alkyl.

[0324] Particularly preferred compounds of formula (I) include:

[0325]4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;

[0326]4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-phenyl-morpholine;

[0327]4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;and

[0328]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;or a

[0329] pharmaceutically acceptable salt thereof.

[0330] An especially preferred compound of formula (I) is

[0331]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyliethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine;

[0332] or a pharmaceutically acceptable salt thereof.

[0333] Further preferred NK-1 receptor antagonists are those describedin PCT International Patent Publication No. WO 95/18124 as compounds offormula (II):

[0334] or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0335] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0336] R² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0337] R³ is hydrogen, halogen or CF₃;

[0338] R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0339] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0340] R⁶ is a 5-membered or 6-membered heterocyclic ring containing 2or 3 nitrogen atoms optionally substituted by ═O, ═S or a C₁₋₄alkylgroup, and optionally substituted by a group of the formula ZNR⁷R⁸ where

[0341] Z is C₁₋₆alkylene or C₃₋₆cycloalkylene;

[0342] R⁷ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl orC₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by C₁₋₄alkoxy orhydroxyl;

[0343] R⁸ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl orC₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by one or twosubstituents selected from C₁₋₄alkoxy, hydroxyl or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S;

[0344] or R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by ahydroxy group, and optionally containing a double bond, which ring mayoptionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂or a second nitrogen atom which will be part of a NH or NR^(c) moietywhere R^(c) is C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy;

[0345] or R⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R⁷ andthe nitrogen atom to which they are attached form a heteroaliphatic ringof 4 to 7 ring atoms which may optionally contain an oxygen ring atom;

[0346] R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄alkyl,

[0347] or R^(9a) and R^(9b) are joined so, together with the carbonatoms to which they are attached, there is formed a C₅₋₇ ring;

[0348] X is an alkylene chain of 1 to 4 carbon atoms optionallysubstituted by oxo; and

[0349] Y is a C₁₋₄alkyl group optionally substituted by a hydroxylgroup; with the proviso that if Y is C₁₋₄alkyl, R⁶ is substituted atleast by a group of formula ZNR⁷R⁸ as defined above.

[0350] Particularly preferred compounds of formula (II) include:

[0351]2-(R)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

[0352](1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((dimethylamino-methyl)-1,2,3-triazol-4-yl)methyl)-3-(S)-(4-fluorophenyl)morpholine;or a pharmaceutically acceptable salt thereof.

[0353] Further preferred NK-1 receptor antagonists are those describedin U.S. Pat. No. 5,691,336 and PCT International Patent Publication No.WO 95/23798 as compounds of formula (III):

[0354] or a pharmaceutically acceptable salt thereof, wherein:

[0355] R² and R³ are independently selected from the group consistingof:

[0356] (1) hydrogen,

[0357] (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0358] (a) hydroxy,

[0359] (b) oxo,

[0360] (c) C₁₋₆ alkoxy,

[0361] (d) phenyl-C₁₋₃ alkoxy,

[0362] (e) phenyl,

[0363] (f) —CN,

[0364] (g) halo,

[0365] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

[0366] (i) hydrogen,

[0367] (ii) C₁₋₆ alkyl,

[0368] (iii) hydroxy-C₁₋₆ alkyl, and

[0369] (iv) phenyl,

[0370] (i) —NR⁹COR¹⁰,

[0371] (j) —NR⁹CO₂R¹⁰,

[0372] (k) —CONR⁹R¹⁰,

[0373] (l) —COR⁹, and

[0374] (m) —CO²R⁹;

[0375] (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0376] (a) hydroxy,

[0377] (b) oxo,

[0378] (c) C₁₋₆ alkoxy,

[0379] (d) phenyl-C₁₋₃ alkoxy,

[0380] (e) phenyl,

[0381] (f) —CN,

[0382] (g) halo,

[0383] (h) —CONR⁹R¹⁰,

[0384] (i) —COR⁹, and

[0385] (j) —CO₂R⁹;

[0386] (4) C₂₋₆ alkynyl;

[0387] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0388] (a) hydroxy,

[0389] (b) C₁₋₆ alkoxy,

[0390] (c) C₁₋₆ alkyl,

[0391] (d) C₂₋₅ alkenyl,

[0392] (e) halo,

[0393] (f) —CN,

[0394] (g) —NO₂,

[0395] (h) —CF₃,

[0396] (i) —(CH₂)_(m)—NR⁹R¹⁰,

[0397] (j) —NR⁹COR¹⁰,

[0398] (k) —NR⁹CO₂R¹⁰,

[0399] (l) —CONR⁹R¹⁰,

[0400] (m) —CO₂NR⁹R¹⁰,

[0401] (n) —COR⁹, and

[0402] (o) —CO₂R⁹;

[0403] and, alternatively, the groups R² and R³ are joined together toform a carbocyclic ring selected from the group consisting of:

[0404] (a) cyclopentyl,

[0405] (b) cyclohexyl,

[0406] (c) phenyl,

[0407] and wherein the carbocyclic ring is unsubstituted or substitutedwith one or more substituents selected from:

[0408] (i) C₁₋₆alkyl,

[0409] (ii) C₁₋₆alkoxy,

[0410] (iii) —NR⁹R¹⁰,

[0411] (iv) halo, and

[0412] (v) trifluoromethyl;

[0413] and, alternatively, the groups R² and R³ are joined together toform a heterocyclic ring selected from the group consisting of.

[0414] (a) pyrrolidinyl,

[0415] (b) piperidinyl,

[0416] (c) pyrrolyl,

[0417] (d) pyridinyl,

[0418] (e) imidazolyl,

[0419] (f) furanyl,

[0420] (g) oxazolyl,

[0421] (h) thienyl, and

[0422] (i) thiazolyl,

[0423] and wherein the heterocyclic ring is unsubstituted or substitutedwith one or more substituent(s) selected from:

[0424] (i) C₁₋₆alkyl,

[0425] (ii) oxo,

[0426] (iii) C₁₋₆alkoxy,

[0427] (iv) —NR⁹R¹⁰,

[0428] (v) halo, and

[0429] (vi) trifluoromethyl;

[0430] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0431] (1) hydrogen;

[0432] (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0433] (a) hydroxy,

[0434] (b) oxo,

[0435] (c) C₁₋₆ alkoxy,

[0436] (d) phenyl-C₁₋₃ alkoxy,

[0437] (e) phenyl,

[0438] (f) —CN,

[0439] (g) halo,

[0440] (h) —NR⁹R¹⁰,

[0441] (i) —NR⁹COR¹⁰,

[0442] (j) —NR⁹CO₂R¹⁰,

[0443] (k) —CONR⁹R¹⁰,

[0444] (l) —COR⁹, and

[0445] (m) —CO₂R⁹;

[0446] (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0447] (a) hydroxy,

[0448] (b) oxo,

[0449] (c) C₁₋₆ alkoxy,

[0450] (d) phenyl-C₁₋₃ alkoxy,

[0451] (e) phenyl,

[0452] (f) —CN,

[0453] (g) halo,

[0454] (h) —CONR⁹R¹⁰,

[0455] (i) —COR⁹, and

[0456] (j) —CO₂R⁹;

[0457] (4) C₂₋₆ alkynyl;

[0458] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0459] (a) hydroxy,

[0460] (b) C₁₋₆ alkoxy,

[0461] (c) C₁₋₆ alkyl,

[0462] (d) C₂₋₅ alkenyl,

[0463] (e) halo,

[0464] (f) —CN,

[0465] (g) —NO₂,

[0466] (h) —CF₃,

[0467] (i) —(Ch₂)_(m)—NR⁹R¹⁰,

[0468] (j) —NR⁹COR¹⁰,

[0469] (k) —NR⁹CO₂R¹⁰,

[0470] (l) —CONR⁹R¹⁰,

[0471] (m) —CO₂NR⁹R¹⁰,

[0472] (n) —COR⁹, and

[0473] (o) —CO₂R⁹;

[0474] (6) halo,

[0475] (7) —CN,

[0476] (8) —CF₃,

[0477] (9) —NO₂,

[0478] (10) —SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅alkyl,

[0479] (11) —SOR¹⁴,

[0480] (12) —SO₂R¹⁴,

[0481] (13) NR⁹COR¹⁰,

[0482] (14) CONR⁹COR¹⁰,

[0483] (15) NR⁹R¹⁰,

[0484] (16) NR⁹CO₂R¹⁰,

[0485] (17) hydroxy,

[0486] (18) C₁₋₆alkoxy,

[0487] (19) COR⁹,

[0488] (20) CO₂R⁹,

[0489] (21) 2-pyridyl,

[0490] (22) 3-pyridyl,

[0491] (23) 4-pyridyl,

[0492] (24) 5-tetrazolyl,

[0493] (25) 2-oxazolyl, and

[0494] (26) 2-thiazolyl;

[0495] R¹¹, R¹² and R¹³ are independently selected from the definitionsof R⁶, R⁷ and R⁸, or —OX;

[0496] A is selected from the group consisting of:

[0497] (1) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0498] (a) hydroxy,

[0499] (b) oxo,

[0500] (c) C₁₋₆ alkoxy,

[0501] (d) phenyl-C₁₋₃ alkoxy,

[0502] (e) phenyl,

[0503] (f) —CN,

[0504] (g) halo,

[0505] (h) —NR⁹R¹⁰,

[0506] (i) —NR⁹COR¹⁰,

[0507] (j) —NR⁹CO₂R¹⁰,

[0508] (k) —CONR⁹R¹⁰,

[0509] (l) —COR^(9,) and

[0510] (m) —CO₂R⁹;

[0511] (2) C₂₋₆ alkenyl, unsubstituted or substituted with one or moreof the substituent(s) selected from:

[0512] (a) hydroxy,

[0513] (b) oxo,

[0514] (c) C₁₋₆ alkoxy,

[0515] (d) phenyl-C₁₋₃ alkoxy,

[0516] (e) phenyl,

[0517] (f) —CN,

[0518] (g) halo,

[0519] (h) —CONR⁹R¹⁰,

[0520] (i) —COR⁹, and

[0521] (j) —CO₂R⁹; and

[0522] (3) C₂₋₆ alkynyl;

[0523] B is a heterocycle, wherein the heterocycle is selected from thegroup consisting of:

[0524] and wherein the heterocycle is substituted in addition to —X withone or more substituent(s) selected from:

[0525] (i) hydrogen;

[0526] (ii) C₁₋₆ alkyl, unsubstituted or substituted with halo, —CF₃,—OCH₃, or phenyl,

[0527] (iii) C₁₋₆ alkoxy,

[0528] (iv) oxo,

[0529] (v) hydroxy,

[0530] (vi) thioxo,

[0531] (vii) —SR⁹,

[0532] (viii) halo,

[0533] (ix) cyano,

[0534] (x) phenyl,

[0535] (xi) trifluoromethyl,

[0536] (Xii) —(Ch₂)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2,

[0537] (xiii) —NR⁹COR¹⁰,

[0538] (xiv) —CONR⁹R¹⁰,

[0539] (xv) —CO₂R⁹, and

[0540] (xvi) —(Ch₂)_(m)—OR⁹;

[0541] p is 0 or 1;

[0542] X is selected from:

[0543] (a) —PO(OH)O⁻.M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

[0544] (b) —PO(O⁻)₂.2M⁺,

[0545] (c) —PO(O⁻)₂.D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

[0546] (d) —CH(R⁴)—PO(OH)O⁻.M⁺, wherein R⁴ is hydrogen or C₁₋₃ alkyl,

[0547] (e) —CH(R⁴)—Po(O⁻)₂.2M⁺,

[0548] (f) —CH(R⁴)—PO(O⁻)₂.D²⁺,

[0549] (g) —SO_(3—).M⁺,

[0550] (h) —CH(R⁴)—SO₃—.M⁺,

[0551] (i) —CO—CH₂CH₂—CO₂.M⁺,

[0552] (j) —CH(CH₃)—O—CO—R⁵, wherein R⁵ is selected from the groupconsisting of:

[0553] (k) hydrogen, with the proviso that if p is 0 and none of R¹¹,R¹² or R¹³ are —OX, then X is other than hydrogen;

[0554] Y is selected from the group consisting of:

[0555] (1) a single bond,

[0556] (2) —O—,

[0557] (3) —S—,

[0558] (4) —CO—,

[0559] (5) —CH₂—,

[0560] (6) —CHR¹⁵—, and

[0561] (7) —CR¹⁵R¹⁶—, wherein R¹⁵ and R¹⁶ are independently selectedfrom the group consisting of:

[0562] (a) C₁₋₆ alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0563] (i) hydroxy,

[0564] (ii) oxo,

[0565] (iii) C₁₋₆ alkoxy,

[0566] (iv) phenyl-C₁₋₃ alkoxy,

[0567] (v) phenyl,

[0568] (vi) —CN,

[0569] (vii) halo,

[0570] (viii) —NR⁹R¹⁰,

[0571] (ix) —NR⁹COR¹⁰,

[0572] (x) —NR⁹CO₂R¹⁰,

[0573] (xi) —CONR⁹R¹⁰,

[0574] (xii) —COR^(9,) and

[0575] (xiii) —CO₂R⁹;

[0576] (b) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0577] (i) hydroxy,

[0578] (ii) C₁₋₆ alkoxy,

[0579] (iii) C₁₋₆ alkyl,

[0580] (iv) C₂₋₅ alkenyl,

[0581] (v) halo,

[0582] (vi) —CN,

[0583] (vii) —NO₂,

[0584] (viii) —CF₃,

[0585] (ix) (Ch₂)_(m)—NR⁹R¹⁰,

[0586] (x) —NR⁹COR¹⁰,

[0587] (xi) —NR⁹CO₂R¹⁰,

[0588] (xii) —CONR⁹R¹⁰,

[0589] (xiii) —CO₂NR⁹R¹⁰,

[0590] (xiv) —COR^(9,) and

[0591] (xv) —CO₂R⁹;

[0592] Z is selected from:

[0593] (1) hydrogen,

[0594] (2) C₁₋₆ alkyl, and

[0595] (3) hydroxy, with the proviso that if Y is —O—, Z is other thanhydroxy, or if Y is —CHR¹⁵—, then Z and R¹⁵ are optionally joinedtogether to form a double bond.

[0596] A particularly preferred compound of formula (III) is2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof. In particular, thebis(N-methyl-D-glucamine) salt is preferred.

[0597] Further preferred NK-1 receptor antagonists are those describedin European Patent Specification No. WO 96/05181, i.e. compounds offormula (IV):

[0598] wherein:

[0599] X is a group of the formula NR⁶R⁷ or a C- or N-linked imidazolylring;

[0600] Y is hydrogen or C₁₋₄alkyl optionally substituted by a hydroxygroup;

[0601] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0602] R² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0603] R³ is hydrogen, halogen or CF₃;

[0604] R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, CF₃,NO₂,CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) are as previously defined;

[0605] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0606] R⁶ is hydrogen, C₁₋₆alkyl, C₃-₇cycloalkyl,C₃-₇cycloalkylC,₄alkyl, phenyl, or C₂ ₄alkyl substituted by C₁₋₄alkoxyor hydroxy;

[0607] R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂A4alkyl substituted by one or twosubstituents selected from C₁₄alkoxy, hydroxy or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S;

[0608] or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated or partially saturated heterocyclic ring of 4to 7 ring atoms, which ring may optionally contain in the ring oneoxygen or sulphur atom or a group selected from NRC, S(O) or S(O)₂ andwhich ring may be optionally substituted by one or two groups selectedfrom hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, oxo, COR^(a) or CO₂R^(a)where R^(a) is as previously defined;

[0609] or R⁶ and R⁷ together with the nitrogen atom to which they areattached, form a non-aromatic azabicyclic ring system of 6 to 12 ringatoms;

[0610] R⁸ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl; and

[0611] R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄-alkyl,or R^(9a) and R^(9b) are joined so, together with the carbon atoms towhich they are attached, there is formed a C₅₋₇ ring;

[0612] and pharmaceutically acceptable salts thereof.

[0613] Specific compounds of formula (IV) of use in the presentinvention include:

[0614]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;

[0615]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0616]4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0617]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;

[0618]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;

[0619]4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0620]2-(R)-(1-(R)-(3,6-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;

[0621]3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;

[0622]3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

[0623]4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

[0624]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;

[0625]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0626]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0627]4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;

[0628]4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;

[0629]2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0630]4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0631]4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0632]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;

[0633] 4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0634]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0635]2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0636]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;

[0637] and pharmaceutically acceptable salts thereof.

[0638] Further preferred NK-1 receptor antagonists are those describedin European Patent Publication No. 0 436 334 as compounds of formula(V):

[0639] or a pharmaceutically acceptable salt thereof, wherein

[0640] Y is (Ch₂)_(n) wherein n is an integer from 1 to 4, and whereinany one of the carbon-carbon single bonds in said (Ch₂)n may optionallybe replaced by a carbon-carbon double bond, and wherein any one of thecarbon atoms of said (Ch₂)n may optionally be substituted with R⁴, andwherein any one of the carbon atoms of said (Ch₂)_(n) may optionally besubstituted with R⁷;

[0641] Z is (Ch₂)m wherein m is an integer from 0 to 6, and wherein anyone of the carbon-carbon single bonds of (Ch₂)_(m) may optionally bereplaced by a carbon-carbon double bond or a carbon-carbon triple bond,and any one of the carbon atoms of said (Ch₂)_(m) may optionally besubstituted with R⁸;

[0642] R¹ is hydrogen or C₁₋₈alkyl optionally substituted with hydroxy,C₁₋₄alkoxy or fluoro;

[0643] R² is a radical selected from hydrogen, C₁₋₆ straight or branchedalkyl, C₃₋₇cycloalkyl wherein one of the CH2 groups in said cycloalkylmay optionally be replaced by NH, oxygen or sulphur; aryl selected fromphenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl-C₂₋₆alkyl, benzhydryl and benzyl,wherein each of said aryl and heteroaryl groups and the phenyl moietiesof said benzyl, phenyl-C₂₋₆alkyl and benzhydryl may optionally besubstituted with one or more substituents independently selected fromhalo, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, trifluoromethyl, amino,C₁₋₆alkylamino, C₁₋₆alkyl-O—CO, C₁₋₆alkyl-O—CO—C₁₋₆alkyl,C₁₋₆alkyl-CO—O, C₁₋₆alkyl-CO—C₁₋₆alkyl-O—, C₁₋₆alkyl-CO,C₁₋₆alkyl-CO—C₁₋₆alkyl-, di-C₁₋₆alkylamino, —CONH—C₁₋₆alkyl,C₁₋₆alkyl-CO—NH—C₁₋₆alkyl, —NHCOH and —NHCO—C₁₋₆alkyl; and wherein oneof the phenyl moieties of said benzhydryl may optionally be replaced bynaphthyl, thienyl, furyl or pyridyl;

[0644] R⁵ is hydrogen, phenyl or C₁₋₆alkyl;

[0645] or R² and R⁵ together with the carbon to which they are attached,form a saturated ring having from 3 to 7 carbon atoms wherein one of theCH₂ groups in said ring may optionally be replaced by oxygen, NH orsulfur;

[0646] R³ is aryl selected from phenyl and naphthyl; heteroaryl selectedfrom indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkylhaving 3 to 7 carbon atoms wherein one of the (Ch₂) groups in saidcycloalkyl may optionally be replaced by NH, oxygen or sulphur;

[0647] wherein each of said aryl and heteroaryl groups may optionally besubstituted with one or more substituents, and said C₃₋₇cycloalkyl mayoptionally be substituted with one or two substituents, each of saidsubstituents being independently selected from halo, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, trifluoromethyl, amino, C₁₋₆alkylamino, —CO—NH—C₁₋₆alkyl,C₁₋₆alkyl-CO—NH—C₁₋₆alkyl, —NHCOH and —NH CO—C₁₋₆alkyl;

[0648] R⁴ and R⁷ are each independently selected from hydroxy, halogen,halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,C₁₋₆alkylamino, di-C₁₋₆alkylamino, C₁₋₆alkoxy, C₁₋₆alkyl-O—CO,C₁₋₆alkyl-O—CO—C₁₋₆alkyl, C₁₋₆alkyl-CO—O, C₁₋₆alkyl-CO—C₁₋₆alkyl-O—,C₁₋₆alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl, and the radicals set forth in thedefinition of R²;

[0649] R⁶ is —NHCOR⁹, —NHCHOR⁹, SO₂R⁸ or one of the radicals set forthin any of the definitions of R², R⁴ and R⁷;

[0650] R⁸ is oximino (═NOH) or one of the radicals set forth in any ofthe definitions of R², R⁴ and R⁷;

[0651] R⁹ is C₁₋₆alkyl, hydrogen, phenyl or phenylC₁₋₆alkyl;

[0652] with the proviso that (a) when m is 0, R⁸ is absent, (b) when R⁴,R⁶, R⁷ or R⁸ is as defined in R², it cannot form together with thecarbon to which it is attached, a ring with R⁵, and (c) when R⁴ and R⁷are attached to the same carbon atom, then either each of R⁴ and R⁷ isindependently selected from hydrogen, fluoro and C₁₋₆alkyl, or R⁴ andR⁷, together with the carbon to which they are attached, for a C3-6saturated carbocyclic ring that forms a spiro compound with thenitrogen-containing ring to which they are attached.

[0653] A particularly preferred compound of formula (V) is(2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or apharmaceutically acceptable salt thereof.

[0654] Another class of NK-1 receptor antagonists is as disclosed in PCTInternational Patent Publication No. WO 93/21155 as compounds of formula(VI):

[0655] or a pharmaceutically acceptable salt thereof, wherein

[0656] radicals R are phenyl radicals optionally 2- or 3-substituted bya halogen atom or a methyl radical;

[0657] R¹ is optionally substituted phenyl, cyclohexadienyl, naphthyl,indenyl or optionally substituted heterocycle;

[0658] R² is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionallysubstituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;

[0659] R³ is optionally 2-substituted phenyl;

[0660] R⁴ is OH or fluorine when R⁵ is H;

[0661] or R⁴ and R⁵ are OH;

[0662] or R⁴ and R⁵ together form a bond.

[0663] A particularly preferred compound of formula (VI) is(3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.

[0664] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in European Patent Publication No. 0 591 040as compounds of formula (VII):

[0665] wherein

[0666] Ar represents an optionally substituted mono-, di- or tricyclicaromatic or heteroaromatic group;

[0667] T represents a bond, a hydroxymethylene group, aC₁₋₄alkoxymethylene group or a C₁₋₅alkylene group;

[0668] Ar′ represents a phenyl group which is unsubstituted orsubstituted by one or more substituents selected from halogen,preferably chlorine or fluorine, trifluoromethyl, C₁₋₄alkoxy, C₁₋₄alkylwhere the said substituents may be the same or different; a thienylgroup; a benzothienyl group; a naphthyl group; or an indolyl group;

[0669] R represents hydrogen, C₁₋₄alkyl, —C₁₋₄alkoxyC₁₋₄alkyl, or-—C₂₋₄alkanoyloxyC₂₋₁4alkyl;

[0670] Q represents hydrogen;

[0671] or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;

[0672] Am⁺ represents the radical

[0673] in which X₁, X₂ and X₃, together with the nitrogen atom to whichthey are attached, form an azabicyclic or azatricyclic ring systemoptionally substituted by a phenyl or benzyl group; and

[0674] A⁻ represents a pharmaceutically acceptable anion.

[0675] A particularly preferred compound of formula (VII) is (+)1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2] octane; or a

[0676] pharmaceutically acceptable salt, especially the chloride,thereof

[0677] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in European Patent Publication No. 0 532 456as compounds of formula (VIII):

[0678] or a pharmaceutically acceptable salt thereof, wherein

[0679] R¹ represents an optionally substituted aralkyl, aryloxyalkyl,heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralka noyl,heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acylgroup of an (-amino acid optionally N-substituted by a lower alkanoyl orcarbamoyl-lower alkanoyl group;

[0680] R² represents cycloalkyl or an optionally substituted aryl orheteroaryl group;

[0681] R³ represents hydrogen, alkyl, carbamoyl or an alkanoyl oralkenoyl group optionally substituted by carboxy or esterified oramidated carboxy;

[0682] R⁴ represents an optionally substituted aryl group or anoptionally partially saturated heteroaryl group;

[0683] X₁ represents methylene, ethylene, a bond, an optionallyketalised carbonyl group or an optionally etherified hydroxymethylenegroup;

[0684] X₂ represents alkylene, carbonyl or a bond; and

[0685] X₃ represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, oran alkyl group optionally substituted by phenyl, hydroxymethyl,optionally esterified or amidated carboxy, or (in other than the(-position) hydroxy.

[0686] A particularly preferred compound of formula (VIII) is(2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine;or a pharmaceutically acceptable salt thereof.

[0687] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in European Patent Publication No. 0 443 132as compounds of formula (IX):

[0688] or a pharmaceutically acceptable salt thereof, wherein

[0689] wherein R¹ is aryl, or a group of the formula:

[0690] or a pharmaceutically acceptable salt thereof, wherein

[0691] X is CH or N; and

[0692] Z is O or N—R⁵, in which R⁵ is hydrogen or lower alkyl;

[0693] R² is hydroxy or lower alkoxy;

[0694] R³ is hydrogen or optionally substituted lower alkyl;

[0695] R⁴ is optionally substituted ar(lower)alkyl;

[0696] A is carbonyl or sulfonyl; and

[0697] Y is a bond or lower alkenylene.

[0698] A particularly preferred compound of formula (IX) is the compoundof formula (IXa)

[0699] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in PCT International Patent Publication No.WO 92/17449 as compounds of the formula (X):

[0700] or a pharmaceutically acceptable salt thereof, wherein

[0701] R¹ is aryl selected from indanyl, phenyl and naphthyl; heteroarylselected from thienyl, furyl, pyridyl and quinolyl; and cycloalkylhaving 3 to 7 carbon atoms, wherein one of said carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; wherein each ofsaid aryl and heteroaryl groups may optionally be substituted with oneor more substituents, and said C₃₋₇cycloalkyl may optionally besubstituted with one or two substituents, said substituents beingindependently selected from chloro, fluoro, bromo, iodo, nitro,C₁₋₁₀alkyl optionally substituted with from one to three fluoro groups,C₁₋₁₀alkoxy optionally substituted with from one to three fluoro groups,amino, C₁₋₁₀alkyl-S—, C₁₋₁₀alkyl-S(O)—, C₁₋₁₀alkyl—SO₂—, phenyl,phenoxy, C₁₋₁₀alkyl—SO₂NH—, C₁₋₁₀alkyl—SO₂NH—C₁₋₁₀alkyl-,C₁₋₁₀alkylamino-diC₁₋₁₀alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7carbon atoms, C₁₋₆alkylamino, C₁₋₆dialkylamino, HC(O)NH— andC₁₋₁₀alkyl-C(O)NH—; and

[0702] R² is thienyl, benzhydryl, naphthyl or phenyl optionallysubstituted with from one to three substituents independently selectedfrom chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbonatoms, C₁₋₁₀alkyl optionally substituted with from one to three fluorogroups and C₁₋₁₀alkoxy optionally substituted with from one to threefluoro groups.

[0703] A particularly preferred compound of formula (X) is(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;or a pharmaceutically acceptable salt thereof.

[0704] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in PCT International Patent Publication No.WO 95/08549 as compounds of formula (XI):

[0705] wherein R¹ is a C₁₋₄alkoxy group;

[0706] R² is

[0707] R³ is a hydrogen or halogen atom;

[0708] R⁴ and R⁵ may each independently represent a hydrogen or halogenatom, or a C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl group;

[0709] R⁶ is a hydrogen atom, a C₁₋₄ alkyl, (Ch₂)_(m) cyclopropyl,—S(O)_(n)C₁₋₄ alkyl, phenyl, NR⁷R⁸, CH₂C(O)CF₃ or trifluoromethyl group;

[0710] R⁷ and R⁸ may each independently represent a hydrogen atom, or aC₁₋₄ alkyl or acyl group;

[0711] x represents zero or 1;

[0712] n represents zero, 1 or 2;

[0713] m represents zero or 1;

[0714] and pharmaceutically acceptable salts and solvates thereof.

[0715] A particularly preferred compound of formula (XI) is[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine;or a pharmaceutically acceptable salt thereof.

[0716] Another class of NK-1 receptor antagonists of use in the presentinvention is that described in PCT International Patent Publication No.WO 97/49710 as compounds of formula (XII):

[0717] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, and X are as definedtherein.

[0718] Particularly preferred compounds of formula (XII) are

[0719](3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5] decane;

[0720](3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;or a pharmaceutically acceptable salt thereof.

[0721] Another class of tachykinin receptor antagonists of use in thepresent invention is that described in PCT International PatentPublication No. WO 95/06645 as compounds of formula (XIII):

[0722] wherein

[0723] R represents a hydrogen atom or a C₁₋₄ alkoxy group;

[0724] R¹ is selected from phenyl, optionally substituted by a group—(CH₂)_(n)CONR³R⁴ or S(O)_(m)R³; or a 5- or 6-membered aromaticheterocycle containing 1, 2, 3 or 4 heteroatoms selected from oxygen,nitrogen, or sulphur, optionally substituted by a C₁₋₄ alkyl,trifluoromethyl or cyano group or a group -(CH₂)_(n)CONR³R⁴;

[0725] R² represents a hydrogen or halogen atom;

[0726] R³ and R⁴ independently represent hydrogen or C₁₋₄ alkyl;

[0727] n represents zero, 1 or 2;

[0728] m represents zero 1 or 2;

[0729] z represents zero or 1;

[0730] and pharmaceutically acceptable salts and solvates thereof.

[0731] A particularly preferred compound of formula (XII) is[5-(5-methyl-tetrazol-1-yl)-benzofuran-7-ylmethyl]-(2S-phenyl-piperidin-3S-yl)-amine;or a pharmaceutically acceptable salt thereof.

[0732] Another class of tachykinin receptor antagonists of use in thepresent invention is that described in PCT International PatentPublication No. WO 95/14017, i.e. compounds of formula (XIV)

[0733] or a pharmaceutically acceptable salt thereof, wherein

[0734] m is zero, 1, 2 or 3;

[0735] n is zero or 1;

[0736] o is zero, 1 or 2;

[0737] p is zero or 1;

[0738] R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl,benzofuiranyl, or naphthyl;

[0739] which R groups may be substituted with one or two halo,C₁₋₃alkoxy, trifluoromethyl, C₁₋₄alkyl, phenyl-C₁₋₃alkoxy, orC₁₋₄alkanoyl groups;

[0740] R¹ is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio,piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl,benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl,quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl,phenyl-(C₁₋₄alkyl)-, phenyl-(C₁₋₄alkoxy)-, quinolinyl-(C₁₋₄alkyl)-,isoquinolinyl-(C₁₋₄alkyl)-, reduced quinolinyl-(C₁₋₄alkyl)-, reducedisoquinolinyl-(C₁₋₄alkyl)-, benzoyl-(C₁₋₃alkyl)-, C₁₋₄alkyl, or—NH—CH₂—R⁵;

[0741] any one of which R¹ groups may be substituted with halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, or C₂₋₄alkanoylamino;

[0742] or any one of which R¹ groups may be substituted with phenyl,piperazinyl, C₃₋₈cycloalkyl, benzyl, C₁₋₄alkyl, piperidinyl, pyridinyl,pyrimidinyl, C₂₋₆alkanoylamino, pyrrolidinyl, C₂₋₆alkanoyl, orC₁₋₄alkoxycarbonyl;

[0743] any one of which groups may be substituted with halo, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,or C₂₋₄alkanoylamino;

[0744] or R¹ is amino, a leaving group, hydrogen, C₁₋₄alkylamino, ordi(C₁₋₄alkyl)amino;

[0745] R⁵ is pyridyl, anilio-(C₁₋₃-alkyl)-, or anilinocarbonyl;

[0746] R² is hydrogen, C₁₋₄alkyl, C₁₋₄alkylsulfonyl,carboxy-(C₁₋₃alkyl)-, C₁₋₃alkoxycarbonyl-(C₁₋₃alkyl)-, or —CO—R⁶;

[0747] R⁶ is hydrogen, C₁₋₄alkyl, C₁₋₃haloalkyl, phenyl, C₁₋₃alkoxy,C₁₋₃hydroxyalkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, or—(CH₂)_(q)—R⁷;

[0748] q is zero to 3;

[0749] R⁷ is carboxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₆alkoxycarbonylamino, or phenoxy,phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl,phenyl-(C₁₋₄alkyl)-, quinolinyl-(C₁₋₄alkyl)-,isoquinolinyl-(C₁₋₄alkyl)-, reduced quinolinyl-(C₁₋₄alkyl)-, reducedisoquinolinyl-(C₁₋₄alkyl)-, benzoyl-C₁₋₃alkyl;

[0750] any one of which aryl or heterocyclic R⁷ groups may besubstituted with halo, trifluoromethyl, C₁₋₄alkoxy, C₁₋₄alkyl, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, or C₂₋₄alkanoylamino;

[0751] or any one of which R⁷ groups may be substituted with phenyl,piperazinyl, C₃₋₈cycloalkyl, benzyl, piperidinyl, pyridinyl,pyrimidinyl, pyrrolidinyl, C₂₋₆alkanoyl, or C₁₋₄alkoxycarbonyl;

[0752] any of which groups may be substituted with halo,trifluoromethyl, amino, C₁₋₄alkoxy, C₁₋₄alkyl, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, or C₂₋₄alkanoylamino;

[0753] R⁸ is hydrogen or C₁₋₆alkyl;

[0754] R³ is phenyl, phenyl-(C₁₋₆alkyl)-, C₃₋₈-cycloalkyl,C₅₋₈cycloalkenyl, C₁₋₈alkyl, naphthyl, C₂₋₈alkenyl, or hydrogen;

[0755] any one or which groups except hydrogen may be substituted withone or two halo, C₁₋₃alkoxy, C₁₋₃alkylthio, nitro, trifluoromethyl, orC₁₋₃alkyl groups; and

[0756] R⁴ is hydrogen or C₁₋₃alkyl;

[0757] with the proviso that if R¹ is hydrogen or halo, R₃ is phenyl,phenyl-(C₁₋₆alkyl)-, C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, or naphthyl.

[0758] A particularly preferred compound of formula (XIII) is[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylamino]propane;or a pharmaceutically acceptable salt thereof.

[0759] The preferred compounds of formulae (I), (II), (III) and (IV)will have the 2- and 3-substituents on the morpholine ring in the cisarrangement, the preferred stereochemistry being as shown in thefollowing general formula:

[0760] Where the benzyloxy moiety is α-substituted, the preferredstereochemistry of the α-carbon is either (R) when the substituent is analkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl(e.g. hydroxymethyl) group.

[0761] The preparation of the foregoing compounds is fully described inthe referenced patents and publications.

[0762] Unless otherwise defined her ein, suitable alkyl groups includestraight-chained and branched alkyl groups containing from 1 to 6 carbonatoms. Typical examples include methyl and ethyl groups, andstraight-chained or branched propyl and butyl groups. Particular alkylgroups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl andtert-butyl.

[0763] Unless otherwise defined herein, suitable alkenyl groups includestraight-chained and branched alkenyl groups containing from 2 to 6carbon atoms. Typical examples include vinyl and allyl groups.

[0764] Unless otherwise defined herein, suitable alkynyl groups includestraight-chained and branched alkynyl groups containing from 2 to 6carbon atoms. Typical examples include ethynyl and propargyl groups.

[0765] Unless otherwise defined herein, suitable cycloalkyl groupsinclude groups containing from 3 to 7 carbon atoms. Particularcycloalkyl groups are cyclopropyl and cyclohexyl.

[0766] Unless otherwise defined herein, suitable aryl groups includephenyl and naphthyl groups. A particular aryl-Cl-6alkyl, e.g.phenyl-C₁₋₆alkyl, group is benzyl.

[0767] Unless otherwise defined herein, suitable heteroaryl groupsinclude pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl,oxadiazolyl and thiadiazolyl groups.

[0768] The term “halogen” as used herein includes fluorine, chlorine,bromine and iodine. The compounds of use in this invention may have oneor more asymmetric centres and can therefore exist as enantiomers andpossibly as diastereoisomers. It is to be understood that the presentinvention relates to the use of all such isomers and mixtures thereof.

[0769] Suitable pharmaceutically acceptable salts of the NK-1 receptorantagonists of use in the present invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundwith a solution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticiacid, citric acid, tartaric acid, carbonic acid, phosphoric acid orsulphuric acid. Salts of amine groups may also comprise the quaternaryammonium salts in which the amino nitrogen atom carries an alkyl,alkenyl, alkynyl or aralkyl group. Where the compound carries an acidicgroup, for example a carboxylic acid group, the present invention alsocontemplates salts thereof, preferably non-toxic pharmaceuticallyacceptable salts thereof, such as the sodium, potassium and calciumsalts thereof.

[0770] The above compounds are only illustrative of the neurokinin-1(NK-1) antagonists which are currently under investigation. As thislisting of compounds is not meant to be comprehensive, the methods ofthe present invention may employ any neurokinin-1 receptor antagonist,in particular a neurokinin-1 receptor antagonist which is orally active,long acting and CNS-penetrant. Accordingly, the present invention is notstrictly limited to any particular structural class of compound.

[0771] Certain of the above defined terms may occur more than once inthe above formula and upon such occurrence each term shall be definedindependently of the other. Similarly, the use of a particular variablewithin a noted structural formula is intended to be independent of theuse of such variable within a different structural formula.

[0772] Full descriptions of the preparation of the tachykinin receptorantagonists which are employed in the present invention may be found inthe references cited herein.

[0773] The present invention accordingly provides the use of a NK-1receptor antagonist selected from the compounds of formulae (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII)and (XIV) for the manufacture of a medicament for treating or preventinga psychosomatic disorder or a psychoimmunologic disorder or amelioratingthe symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient.

[0774] The present invention also provides a method for treating orpreventing a psychosomatic disorder or a psychoimmunologic disorder orameliorating the symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient, which method comprisesadministration to a patient in need of such treatment an effectiveamount of a NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII) and (XIV).

[0775] In a further aspect of the present invention, there is provided apharmaceutical composition for treating or preventing a psychosomaticdisorder or a psychoimmunologic disorder or ameliorating the symptomsattendant to a psychosomatic disorder or a psychoimmunologic disorder ina patient comprising a NK-1 receptor antagonist selected from thecompounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), (XI), (XII), (XIII) and (XIV), together with at least onepharmaceutically acceptable carrier or excipient.

[0776] The identification of a compound as a tachykinin receptorantagonist, in particular, a neurokinin-1 receptor antagonist, and thusable to have utility in the present invention may be readily determinedwithout undue experimentation by methodology well known in the art.

[0777] It is well recognized in the art that psychological stimuli canprecipitate or alter the course of numerous diseases or disorders. Asused herein a “psychosomatic disorder” is a disease or disorder forwhich the physical etiology is contributed to directly or indirectly bypsychological factors. As used herein a “psychoimmunologic disorder” isan immunologic disease or disorder wherein an immunological response isinfluenced directly or indirectly by psychological factors.

[0778] Accordingly, the present invention provides methods for thetreatment or prevention of a psychosomatic disorder or a psycho-immunologic disorder wherein the physical etiology or immunologicalresponse is contributed to directly or indirectly by psychologicalfactors in the origin or progression of diseases and disorders such asalopecia areata, angina pectoris nervosa, asthma, atopoic dermatitis,autonomic imbalance, bacterial infections, bronchial asthma, cancer,cerebrovascular disease, collage vascular diseases, diabetes mellitus,duodenal ulcer, dyspnoeneurosis, essential hypertension, gastric ulcer,hypersensitive skin response, hypertension, inflammatory skin disorders,leukemia, malignancy, multiple sclerosis, myocardial infarction,neurodermatitis, neurotic emesis, peptic ulcer, psoriasis, puritis,respiratory illness, rheumatoid arthritis, systemic lupus erythematosus,thyrotoxicosis, ulcreative colitis, varicella zoster, and viralinfection. As will be readily appreciated by one skilled in the art,psychological pressures which contribute to the clinical course of suchpsychosomatic or psychoimmunologic diseases and disorders may be only acontributing factor to the penultimate state of the disorder or disease.In addition, the psychological pressures which contribute to theclinical course of such psychosomatic or psychoimmunologic diseases anddisorders interact with numerous other factors, including the patient'shereditary predisposition, personality features, and the autonomic andendocrine effects that arise in response to individual vicissitudes.

[0779] A tachykinin receptor antagonist may be administered alone or incombination by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous or subcutaneous injection, or implant), nasal, vaginal,rectal, sublingual, or topical routes of administration and can beformulated in dosage forms appropriate for each route of administration.

[0780] Preferably the compositions according to the present inventionare in unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, by inhalation or insufflation oradministration by trans-dermal patches or by buccal cavity absorptionwafers.

[0781] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

[0782] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, peanut oil or soybean oil, as well aselixirs and similar pharmaceutical vehicles. Suitable dispersing orsuspending agents for aqueous suspensions include synthetic and naturalgums such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone orgelatin.

[0783] Preferred compositions for administration by injection includethose comprising a NK-1 receptor antagonist as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

[0784] Suitable surface-active agents include, in particular, non-ionicagents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositionswith a surface-active agent will conveniently comprise between 0.05 and5% surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

[0785] Suitable emulsions may be prepared using commercially availablefat emulsions, such as Intralipid™, Ljposyn™, Infonutrol™, Lipofundin™and Lipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

[0786] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[0787] Compositions of the present invention may also be presented foradministration in the form of trans-dermal patches using conventionaltechnology. The compositions may also be administered via the buccalcavity using, for example, absorption wafers.

[0788] Compositions in the form of tablets, pills, capsules or wafersfor oral administration are particularly preferred.

[0789] It will be known to those skilled in the art that there arenumerous compounds which may be used for treating or preventing apsychosomatic disorder or a psychoimmunologic disorder in a patient.Combinations of these therapeutic agents some of which have also beenmentioned herein with a tachykinin receptor antagonist will bringadditional, complementary, and often synergistic properties to enhancethe desirable properties of these various therapeutic agents. In thesecombinations, the tachykinin receptor antagonist and the therapeuticagents may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when thesecompounds are used singly. In such combination therapy, the tachykininreceptor antagonist may be administered with the other therapeutic agent(e.g., concurrently, concombinantly, sequentially, or in a unitaryformulation) such that their therapeutic efficacy overlap.

[0790] The tachykinin receptor antagonist may be administered incombination with stimulants, hypnotics, anxiolytics, antipsychotics,antianxiety agents, minor tranquilizers, benzodiazepines, barbituates,serotonin agonists, selective serotonin reuptake inhibitors, 5HT-2antagonists, non-steroidal anti-inflammatory drugs, oral contraceptives,progesterone, progestin, monoamine oxidase inhibitors, and the like, orthe tachykinin receptor antagonist may be administered in conjunctionwith the use of physical methods such as electrical stimulation.

[0791] For example, for treating or preventing a psychosomatic disorderor a psychoimmunologic disorder in a patient a tachykinin receptorantagonist may be given in combination with such compounds as:adinazolam, allobarbital, alonimid, alprazolam, amitriptyline,amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, caffeine, capuride, carbocloral,chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine,cloperidone, clorazepate, clorethate, clozapine, cyprazepam, deanol,desipramine, dexclamol, dextroamphetamine, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, methylphenidate, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam,paraldehyde, paroxetine, pemoline, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,valproate, venlafaxine, zaleplon, zolazepam, zolpidem, and saltsthereof, and combinations thereof, and the like, as well as admixturesand combinations thereof.

[0792] Typically, the individual daily dosages for these combinationsmay range from about one-fifth of the minimally recommended clinicaldosages to the maximum recommended levels for the entities when they aregiven singly. In the case of methylphenidate the recommended clinicaldose is generally from approximately 5 mg/day to approximately 20mg/day, however, the dosage may be titrated, beginning at low doses andincreasing to optimal levels (decrease in symptoms, improvement in taskperformance, and no side effects).

[0793] To illustrate these combinations, a tachykinin receptorantagonist effective clinically at a given daily dose range may beeffectively combined, at levels which are equal or less than the dailydose range, with the aforementioned compounds. It will be readilyapparent to one skilled in the art that the tachykinin receptorantagonist may be employed with other agents for treating or preventinga psychosomatic disorder or a psychoimmunologic disorder or amelioratingthe symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient.

[0794] Naturally, these dose ranges may be adjusted on a unit basis asnecessary to permit divided daily dosage and, as noted above, the dosewill vary depending on the nature and severity of the disease, weight ofpatient, special diets and other factors. These combinations may beformulated into pharmaceutical compositions as known in the art and asdiscussed herein.

[0795] The dosage of active ingredient in the compositions of thisinvention may be varied, however, it is necessary that the amount of theactive ingredient be such that a suitable dosage form is obtained. Theactive ingredient may be administered to patients (animals and human) inneed of such treatment in dosages that will provide optimalpharmaceutical efficacy. The selected dosage depends upon the desiredtherapeutic effect, on the route of administration, and on the durationof the treatment. The dose will vary from patient to patient dependingupon the nature and severity of disease or disorder, the patient'sweight, special diets then being followed by a patient, concurrentmedication, the intrinsic tachykinin receptor antagonist activity of thecompound, the bioavailability upon oral administration of the compoundand other factors which those skilled in the art will recognize.

[0796] In the treatment of a condition in accordance with the presentinvention, an appropriate dosage level will generally be about 0.01 ggto 50 mg per kg patient body weight per day which may be administered insingle or multiple doses. Preferably, the dosage level will be about 0.1μg to about 25 mg/kg per day; more preferably about 0.5 μg to about 10mg/kg per day. For example, for treating or preventing a psychosomaticdisorder or a psychoimmunologic disorder or ameliorating the symptomsattendant to a psychosomatic disorder or a psychoimmunologic disorder ina patient, a suitable dosage level is about 0.1 μg to 25 mg/kg per day,preferably about 0.5 μg to 10 mg/kg per day, and especially about 1 μgto 5 mg/kg per day. In larger mammals, for example humans, a typicalindicated dose is about 300 μg to 400 mg orally. A compound may beadministered on a regimen of several times per day, for example 1 to 4times per day, preferably once or twice per day. When using aninjectable formulation, a suitable dosage level is about 0.1 μg to 10mg/kg per day, preferably about 0.5 μg to 5 mg/kg per day, andespecially about 1 μg to 1 mg/kg per day. In larger mammals, for examplehumans, a typical indicated dose is about 100 μg to 100 mg i.v. Acompound may be administered on a regimen of several times per day, forexample 1 to 4 times per day, preferably once or twice per day, and morepreferably once a day.

[0797] Pharmaceutical compositions of the present invention may beprovided in a solid dosage formulation preferably comprising about 100μg to 500 mg active ingredient, more preferably comprising about 100 μgto 250 mg active ingredient. The pharmaceutical composition ispreferably provided in a solid dosage formulation comprising about 100μg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 300 mg activeingredient. A minimum dosage level for the NK-1 receptor antagonist isgenerally about 5mg per day, preferably about 10mg per day andespecially about 20mg per day. A maximum dosage level for the NK-1receptor antagonist is generally about 1500mg per day, preferably about1000mg per day and especially about 500mg per day.

[0798] It will be appreciated that the amount of the NK-1 receptorantagonist required for use in treating or preventing a psychosomaticdisorder or a psychoimmunologic disorder or ameliorating the symptomsattendant to a psychosomatic disorder or a psychoimmunologic disorder ina patient will vary not only with the particular compounds orcompositions selected but also with the route of administration, thenature of the condition being treated, and the age and condition of thepatient, and will ultimately be at the discretion of the patient'sphysician or pharmacist. The length of time during which a tachykininreceptor antagonist will be given varies on an individual basis.

[0799] The compounds of formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) may be preparedby the methods described in EP-A-0 577 394 (or WO 95/16679), WO95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549, WO97/49710, WO 95/06645 and WO 95/14017, respectively.

[0800] Particularly preferred NK-1 receptor antagonists of the formulae(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),(XII), (XIII) and (XIV) for use in the present invention are compoundswhich are potent NK-1 receptor antagonists, i.e. compounds with an NK-1receptor affinity (IC₅₀) of less than 10 nM.

[0801] A particularly preferred class of NK-1 receptor antagonist of usein the present invention are those compounds which are orally active,long acting and CNS-penetrant. Such compounds may be identified usingthe pharmacological assays described hereinafter. The use of thissub-class of NK-1 antagonists for treating or preventing a psychosomaticdisorder or a psychoimmunologic disorder or ameliorating the symptomsattendant to a psychosomatic disorder or a psychoimmunologic disorder ina patient represents a further aspect of the present invention.

[0802] Thus, the present invention provides the use of a CNS penetrantNK-1 receptor antagonist in an oral, once-a-day medicament for treatingor preventing a psychosomatic disorder or a psychoimmunologic disorderor ameliorating the symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient. The compounds of this classadvantageously exhibit a rapid onset of action and a reduced side-effectprofile when compared against conventional methods for treating orpreventing a psychosomatic disorder or a psychoimmunologic disorder in apatient.

[0803] In particular, the present invention provides a means for theidentification of NK-1 receptor antagonists which would be especiallyeffective in an oral once-a-day medicament for treating or preventing apsychosomatic disorder or a psychoimmunologic disorder or amelioratingthe symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient.

[0804] The exceptional pharmacology of the class of NK-1 receptorantagonists of use in the present invention enables treating orpreventing a psychosomatic disorder or a psychoimmunologic disorder orameliorating the symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient, without the need forconcomitant therapy and in particular, without the need for concomitantuse of a serotonin agonist or an SSRI.

[0805] Furthermore, the exceptional pharmacology of the class of NK-1receptor antagonists of use in the present invention results in a rapidonset of action.

[0806] The present invention accordingly provides the use of an orallyactive, long acting, CNS-penetrant NK-1 receptor antagonist (ashereinafter defined) for the manufacture of a medicament adapted fororal administration for treating or preventing a psychosomatic disorderor a psychoimmunologic disorder or ameliorating the symptoms attendantto a psychosomatic disorder or a psychoimmunologic disorder in apatient.

[0807] The present invention also provides a method for treating orpreventing a psychosomatic disorder or a psychoimmunologic disorder orameliorating the symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient, which method comprises the oraladministration to a patient in need of such treatment of an effectiveamount of an orally active, long acting, CNS-penetrant NK-1 receptorantagonist (as defined herein).

[0808] In a further aspect of the present invention, there is providedan oral pharmaceutical composition for treating or preventing apsychosomatic disorder or a psychoimmunologic disorder or amelioratingthe symptoms attendant to a psychosomatic disorder or apsychoimmunologic disorder in a patient which comprises an orallyactive, long acting, CNS-penetrant NK-1 receptor antagonist (ashereinafter defined), together with a pharmaceutically acceptablecarrier or excipient.

[0809] It will be appreciated to those skilled in the art that referenceherein to treatment extends to prophylaxis (prevention) as well as thetreatment of the noted diseases/disorders and symptoms. Because thespecific diagnosis of a psychosomatic disorder or a psychoimmunologicdisorder in a particular patient may be difficult, the patient maybenefit from the prophylactic administration of a subject compound inaccordance with the present invention Preferred NK-1 receptorantagonists for use in the present invention as orally active, longacting, CNS-penetrant NK-1 receptor antagonists are selected from theclasses of compounds described in European Patent Specification No. 0577 394, and International Patent Specification Nos. 95/08549, 95/18124,95/23798, 96/05181 and WO 97/49710.

[0810] Particularly preferred NK-1 receptor antagonists of use in thepresent invention include:

[0811] (±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3amine;

[0812] 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;

[0813]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

[0814]2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

[0815]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;

[0816] 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

[0817]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

[0818] (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;

[0819] (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;

[0820]2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;

[0821]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0822]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0823]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0824]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;

[0825]2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;

[0826]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0827] or a pharmaceutically acceptable salt thereof Full descriptionsof the preparation of the tachykinin receptor antagonists which may beemployed in the present invention may be found in the references citedherein.

[0828] The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

EXAMPLE 1

[0829] NK-1 Receptor binding Assay

[0830] NK-1 receptor binding assays are performed in intact Chinesehamster ovary (CHO) cells expressing the human NK-1 receptor using amodification of the assay conditions described by Cascieri et al, J.Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor isexpressed at a level of 3x105 receptors per cell. Cells are grown inmonolayer culture, detached from the plate with enzyme-free dissociationsolution (Speciality Media Inc.), and washed prior to use in the assay.¹²⁵I-Tyr⁸-substance P (0.1 nM, 2000 Ci/mmol; New England Nuclear) isincubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5×10⁴ CHO cells. Ligand binding isperformed in 0.25 ml of 50 mM Tris-HCl, pH7.5, containing 5 mM MnCl₂, 50mM NaCl, 0.02% bovine serum albumin (Sigma), 50 μg/ml chymostatin(Peninsula), 0.1 nM phenylmethylsulphonyl fluoride, 2 μg/ml pepstatin, 2μg/ml leupeptin and 2.8 μg/ml furoyl saccharine. The incubation proceedsat room temperature until equilibrium is achieved (>40 minutes) and thereceptor-ligand complex is harvested by filtration over GF/C filterspre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester.Non-specific binding is determined using excess substance P (1 μM) andrepresents <10% of total binding.

EXAMPLE 2

[0831] Gerbil Foot-Tapping Assay

[0832] CNS penetrant NK-1 receptor antagonists for use in the presentinvention can be identified by their ability to inhibit foot tapping ingerbils induced by anxiogenic agents (such as pentagastrin) or centralinfusion of NK-1 receptor agonists such as GR73632, or caused byaversive stimulation such as foot shock or single housing, based on themethod of Rupniak & Williams, Eur. J. Pharmacol., 1994, 265, 179.

[0833] Male or female Mongolian gerbils (35-70g) are anaesthetised byinhalation of an isoflurane/oxygen mixture to permit exposure of thejugular vein in order to permit administration of test compounds orvehicle in an injection volume of 5 ml/kg i.v. Alternatively, testcompounds may be administered orally or by subcutaneous orintraperitoneal routes. The wound is closed and a second skin incisionis made in the midline of the scalp to expose the skull. An anxiogenicagent (e.g. pentagastrin) or a selective NK-1 receptor agonist (e.g.GR73632 (d Ala[L-Pro⁹,Me-Leu¹⁰]-substance P-(7-11))) is infused directlyinto the cerebral ventricles (e.g. 3 pmol in 5 μl i.c.v. depending uponthe agent) by vertical insertion of a cuffed 27 gauge needle to a depthof 4.5 mm below bregma. The scalp incision is closed and the animalallowed to recover from anaesthesia in a clear perspex observation box(25 cm×20 cm×20 cm). The duration and/or intensity of hind foot tappingis then recorded continuously for 5 minutes. Alternatively, the abilityof test compounds to inhibit foot tapping evoked by aversivestimulation, such as foot shock or single housing, may be studied usinga similar method of quantification.

EXAMPLE 3

[0834] Ferret Emesis Assay

[0835] Individually housed male ferrets (1.0-2.5 kg) are dosed orally bygavage with test compound. Ten minutes later they are fed withapproximately 100 g of tinned cat food. At 60 minutes following oraldosing, cisplatin (10 mg/kg) is given i.v. via a jugular vein catheterinserted under a brief period of halothane anaesthesia. The catheter isthen removed, the jugular vein ligated and the skin incision closed. Theferrets recover rapidly from the anaesthetic and are mobile within 10-20minutes. The animals are observed continuously during recovery from theanaesthetic and for 4 hours following the cisplatin injection, afterwhich time the animals are killed humanely. The numbers of retches andvomits occurring during the 4 hours after cisplatin administration arerecorded by trained observers.

EXAMPLE 4

[0836] Separation-Induced Vocalisation Assay

[0837] Male and female guinea-pigs pups are housed in family groups withtheir mothers and littermates throughout the study. Experiments arecommenced after weaning when the pups are 2 weeks old. Before enteringan experiment, the pups are screened to ensure that a vigorousvocalisation response is reproducibly elicited following maternalseparation. The pups are placed individually in an observation cage (55cm×39 cm×19 cm) in a room physically isolated from the home cage for 15minutes and the duration of vocalisation during this baseline period isrecorded. Only animals which vocalise for longer than 5 minutes areemployed for drug challenge studies (approximately 50% of available pupsmay fail to reach this criterion). On test days each pup receives anoral dose or a s.c. or i.p. injection of test compound or vehicle and isthen immediately returned to the home cage with its mother and siblingsfor 30 minutes to 60 minutes (or for up to 4 hours following an oraldose, dependant upon the oral pharmacokinetics of the test compound)before social isolation for 15 minutes as described above. The durationof vocalisation on drug treatment days is expressed as a percentage ofthe pre-treatment baseline value for each animal. The same subjects areretested once weekly for up to 6 weeks. Between 6 and 8 animals receiveeach test compound at each dose tested.

[0838] A suitable selection cascade for NK₁ antagonists of use accordingto the present invention is as follows:

[0839] (i) Determine affinity for human NK₁ receptor in radioligandbinding studies (Assay 1); select compounds with IC₅₀≦10 nM, preferablyIC₅₀≦2 nM, especially IC₅₀≦1 nM.

[0840] (ii) Determine ability of compounds to penetrate CNS by theirability to inhibit foot tapping in gerbils induced by central injectionof an NK₁ agonist (Assay 2); select compounds that inhibit foot tappingwith ID₅₀≦3 mg/kg i.v., and preferably ID₅₀≦1 mg/kg i.v. whenadministered immediately prior to central NK₁ agonist challenge, orID₅₀≦30 mg/kg p.o., and preferably ID₅₀≦10 mg/kg p.o. 1 hour prior tochallenge.

[0841] (iii) Determine central duration of action of compounds in gerbilfoot tapping assay following intravenous administration 24 hours priorto central NK₁ agonist challenge; select compounds showing ≦25-fold lossof potency compared with ID₅₀ determined in step (ii) above with theproviso that ID₅₀≦10 mg/kg i.v., and preferably ≦5 mg/kg i.v. after 24hour pre-treatment.

[0842] (iv) Determine oral bioavailability of compounds bypharmacokinetic analysis, activity in gerbil foot tapping assayfollowing oral administration and/or by ability to inhibitcisplatin-induced emesis in ferrets (Assay 3); select compounds withID₉₀<3 mg/kg p.o., and preferably ID₉₀≦1 mg/kg p.o.

[0843] Particularly preferred compounds of use in the present inventionare identified using steps (i) to (iv) followed by step (v):

[0844] (v) Determine activity of compounds in assays sensitive toconventional antidepressant drugs (inhibition of pharmacologicallyevoked foot tapping in gerbils and/or inhibition of distressvocalisations in guinea-pig pups (Assay 4)). Select compounds withID₅₀≦20 mg/kg, and preferably ID₅₀≦10 mg/kg.

[0845] Yet further preferred compounds of use in the present inventionmay be selected from those compounds which satisfy the NK-1 receptorbinding criteria of step (i) which, in addition, have ≦5-fold shift inaffinity when incubated in the presence of human serum albumin (HSA) toshow non-specific protein binding.

[0846] One example of a NK-1 receptor antagonist of use in the presentinvention is the compound2-(R)-(1-(R)-(3,5-bis(trifiuoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-morpholine,the preparation of which is described in PCT Patent Publication No. WO95/16679. In the aforementioned assays, this compound has the followingactivity: human NK-1 receptor binding: IC₅₀ = 0.1 nM gerbil foot-tapping(5 mins.): ID₅₀ = 0.36 mg/kg i.v. gerbil foot-tapping (24 hrs.): ID₅₀ =0.33 mg/kg i.v. ferret emesis: ID₉₀ < 3 mg/kg p.o. guinea-pigvocalisation ID₅₀ = 0.73 mg/kg p.o. (4 hr. pre-treatment):

[0847] The following example illustrates pharmaceutical compositionsaccording to the invention.

EXAMPLE 5

[0848] Tablet formulation containing 50-300 mg of NK-1 antagonist Amountmg NK-1 antagonist 50.0 100.0 300.0 Microcrystalline cellulose 80.0 80.080.0 Modified food corn starch 80.0 80.0 80.0 Lactose 189.5 139.5 439.5Magnesium Stearate 0.5 0.5 0.5

[0849] The active ingredient, cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 50 mg, 100 mg and 300 mg of theNK-1 receptor antagonist per tablet.

EXAMPLE 6

[0850] Parenteral injection formulation Amount Active Ingredient 10 to300 mg Citric Acid Monohydrate 0.75 mg Sodium Phosphate 4.5 mg SodiumChloride 9 mg Water for injection to 10 ml

[0851] The sodium phosphate, citric acid monohydrate and sodium chlorideare dissolved in a portion of the water. The active ingredient isdissolved or suspended in the solution and made up to volume.

EXAMPLE 7

[0852] Double-Blind, Placebo-Controlled Study to Determine the Effect ofa Neurokinin-1 Antagonist on Patients Suffering from a PsychosomaticDisorder or a Psychoimmunologic Disorder

[0853] Approximately twenty patients suffering from a psychosomaticdisorder or a psychoimmunologic disorder receive either the neurokinin-1receptor antagonist2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine(30 mg/day) or a placebo. Each subject participates in 6 randomized testperiods; in 3 of the test periods, each is given the substance Pantagonist and in the other 3 test periods, is given a placebo. Efficacyof the test compound is assessed by reference to immunological profile,rating scales, checklists and diminishment of the attendant diseasestate. The results of the foregoing study would indicate that theadministration of a neurokinin-1 receptor antagonist would be expectedto have a positive effect with respect to placebo in the treatment orprevention of a psychosomatic disorder or a psychoimmunologic disorderor tbe amelioration of symptoms attendant to a psychosomatic disorder ora psychoimmunologic disorder following drug treatment.

[0854] While the invention has been described and illustrated withreference to certain particular embodiments thereof, those skilled inthe art will appreciate that various adaptations, changes,modifications, substitutions, deletions, or additions of procedures andprotocols may be made without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A method for the treatment or prevention of apsychosomatic disorder in a patient which comprises administering aneffective amount of a tachykinin receptor antagonist.
 2. The method ofclaim 1 wherein the tachykinin receptor antagonist is a neurokinin-1receptor antagonist.
 3. The method of claim 2 wherein the neurokinin-1receptor antagonist is a CNS-penetrating neurokinin-1 receptorantagonist.
 4. The method of claim 3 wherein the neurokinin-1 receptorantagonist is an orally active neurokinin-1 receptor antagonist.
 5. Themethod of claim 4 wherein the neurokinin-1 receptor antagonist possessesa long duration of action.
 6. The method of claim 2 wherein theneurokinin-1 receptor antagonist is a non-peptidal neurokinin-1 receptorantagonist.
 7. A method for the treatment or prevention of apsychoimmunologic disorder in a patient which comprises administering aneffective amount of a tachykinin receptor antagonist.
 8. The method ofclaim 7 wherein the tachykinin receptor antagonist is a neurokinin-1receptor antagonist.
 9. The method of claim 8 wherein the neurokinin-1receptor antagonist is a CNS-penetrating neurokinin-1 receptorantagonist.
 10. The method of claim 9 wherein the neurokinin-1 receptorantagonist is an orally active neurokinin-1 receptor antagonist.
 11. Themethod of claim 10 wherein the neurokinin-1 receptor antagonistpossesses a long duration of action.
 12. The method of claim 7 whereinthe neurokinin-1 receptor antagonist is a non-peptidal neurokinin-1receptor antagonist.